This program is focused upon ocular surface immune-mediated diseases. We continue to study the etiology and pathogenesis of ocular surface inflammation in keratoconjunctivitis sicca and have recently published our findings on an EDA (ectodysplasin) mouse model which lacks meibomian glands and develops severe corneal scarring and neovascularization, resulting in blindness. EDA is required for the formation of ectoderm-derives tissues and in the EDA mutant Tabby mouse we have described characteristic ocular surface abnormalities and through transgenic studies, demonstrated that the corneal defects and inflammation were prevented in EDA transgenic mice even though Meibomian glands were restored little if at all. This implies that EDA may be important in susceptibility to inflammation which may occur through activation of nuclear factor-kappa B transcription factors. We also published our findings of helicobacter pylori DNA in conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and theorize that exposure to patterns expressed by pathogens such as H. pylori can stimulate chronic indolent inflammation and lymphomagenesis in the eye. This opens the door to antibiotic eradication therapy and as adjunct treatment of conjunctival MALT lymphoma. We have also been investigating the treatment of the autoimmune exocrinopathy, Sjogren's Syndrome, which is associated with a particularly severe form of dry eye in which the pathogenesis may include sex hormone insufficiency and dysregulated immune regulation. Thalidomide was poorly tolerated and the protocol was closed. We published the results of a 24 week randomized, double-masked, placebo controlled pilot study of DHEA (200 mg/day) in patients with primary Sjogren?s syndrome. Response criteria required 20% improvement in at least 2/3 domains: ocular and oral signs, and sicca symptoms. There was significant improvement only in oral dryness symptoms with DHEA treatment. Further we published the results of a 12 week randomized, double-masked, placebo-controlled trail of twice-weekly 25 mg etanercept subcutaneous injection. Although serum inflammatory markers were significantly reduced in the etanercept treated patients, they were no other significant differences. We are continuing to study a unique form of ocular surface disease associated with Premature Ovarian Failure that we first reported and recently published and are evaluating the ocular response to systemic testosterone treatment of these women in a placebo-controlled, randomized controlled trial. As part of our interest in outcome measures for ocular surface disease, we examined the associations between vision-targeted health related quality of life and ocular surface parameters in Sjogren?s syndrome. We found the associations between conventional objective measure of dry eye and both the NEI- visual function questionnaire and the disease-specific, Ocular Surface Disease Index, to be modest. This suggests that improvement is needed in the understanding of and objective assessment of the features of ocular surface disease responsible for symptoms. In our continued work on validation of outcome measures for ocular surface disease, we have published our findings which will facilitate future randomized controlled trials of treatments for Sjogren?s syndrome and dry eye. This work is ongoing.